Heparin and its derivatives have shown promise in treating inflammatory diseases. Heparin and its derivatives disrupt at least three important events in inflammatory cascades. First, heparin attaches to and blocks the leukocyte integrins P- and L-selectin. Second, heparin and its derivatives reduce the inflammatory cascade by binding to and inhibiting the cationic PMN protease human leukocyte elastase and cathepsin G, which reduces proteolytic tissue injury by PMNs that escape the first heparin barrier of selectin inhibition. Third, heparin and its derivatives potentially inhibit the interaction of the receptor for advanced glycation end-products (RAGE) with its ligands. However, treatments using heparin and its derivatives exhibiting anticoagulant activity have several major drawbacks. First, heparin and its derivatives are porcine-derived; thus leading to concerns of cross-species transfer of viruses. Second, because of their anticoagulant properties, diabetics treated with this compound are at risk of excessive bleeding. Third, heparin or some of its derivatives may induce thrombocytopenia in certain individuals who produce an antibody to the complex of heparin with the cationic protein platelet factor-4 (PF-4), resulting in catastrophic platelet aggregation and generalized paradoxical arterial and venous clotting. Thus, there exists an important unmet need for compounds which may be used to treat inflammatory diseases while avoiding the myriad of side effects seen from treatments using heparin or heparin-like agents.
Inflammatory diseases such as psoriasis, dermatitis, acne, rosacea, photo-dermal ageing, and numerous diseases linked to RAGE-mediated signaling, plague people worldwide. To put these diseases into perspective, the National Psoriasis Foundation reports that psoriasis alone afflicts 2-3% of the world's population or approximately 125 million people. These inflammatory conditions can be aesthetically unpleasing and can create serious health issues if left untreated. Conventionally accepted treatments of these conditions may involve UV phototherapy, corticosteroids and glucocorticoids, acitretin, cyclosporine, and methotrexate. However, each of these treatments may cause serious side effects ranging from immune suppression and liver disease to thinning skin and causing birth defects. Due to partial or complete ineffectiveness, these treatments often leave patients unsatisfied with their results.
Inflammatory responses may also contribute to certain ocular or ophthalmic conditions, including age-related macular degeneration, diabetic retinopathy, dry eye syndrome and other inflammatory conjunctivitis, iritis, uveitis, allergic conjunctivitis, anti-inflammatory aid in cataract surgery, or in the prevention of corneal inflammation and scarring.
Dry eye disease is a multi-factorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. Dry eye results from decreased production, increased evaporation, or decreased clearance of tears and if left untreated, can lead to pain, blurred and fluctuating vision and an increased risk of sight-threatening corneal infection and ulceration, scars on the cornea, and some loss of vision.
Dry eye is a common condition that affects over 20 million individuals in the US or 10% of the population between the ages of 30 and 60 years, with increasing prevalence to 15% of the population aged more than 65 years. There are numerous causes of dry eye including various systemic diseases, systemic medications, hormonal changes, neural alterations, and environmental influences. Treatment options may follow different approaches, depending on the cause of the disease and include treatment of the underlying associated conditions. Due to the many different causes and pathophysiologies, dry eye treatment continues to present a substantial challenge to the clinician.
Over-the-counter ocular lubricants remain the mainstay of treatment and hyaluronic acid based products are key therapeutic alternatives in Japan and the EU. A formulation of 0.05% cyclosporine A (Restasis®) is the only Food and Drug Administration (FDA) approved ophthalmic solution for dry eye. Cyclosporine A is an immunomodulator whose mechanism of action appears to be associated with suppression of inflammation associated with keratoconjunctivitis sicca, however, it has limited efficacy and a significant number of users experience side effects. Only 15% of Restasis® ophthalmic emulsion treated patients, versus 5% of vehicle treated patients had a significant increase in tear production, as defined in clinical studies leading to drug approval. The most commonly reported adverse event following the use of Restasis® is ocular burning, present in approximately 17% of users. Other events reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging and visual disturbance (most often blurring).
There is a clear unmet medical need for more effective, safer and convenient treatment options for ocular or ophthalmic conditions, including dry eye disease. A product that targets these conditions, e.g., one or more of the multiple aspects of the complex dry eye physiopathology, can have significant clinical benefit.